This invention relates to the diagnosis of glomerulonephritis.
Glomerulonephritis is a renal disease characterized by bilateral inflammatory changes in the glomeruli of the kidneys. Rapidly progressive glomerulonephritis (RPGN) can be caused by any of several underlying conditions, including: necrotizing and/or crescentic glomerulonephritis with scant or no immune deposits (pauci-immune NCGN), anti-glomular basement membrane nephritis (anti-GBM nephritis), IgA nephropathy, lupus nephritis, and post-streptococcal glomerulonephritis. In addition, certain diseases other than glomerulonephritis, such as the hemolytic uremic syndrome or acute interstitial nephritis, may produce the clinical picture of RPGN. Pauci-immune NCGN can be restricted to the kidney (primary NCGN) or associated with Wegener's granulomatosis or a systemic disease often classified as microscopic polyarteritis nodosa.
Diagnosis of the condition causing RPGN is essential for the initiation of appropriate treatment to prevent or reverse deterioration of renal function. Renal biopsy has generally been considered to be the most definite diagnostic procedure in patients exhibiting RPGN. However, the procedure involved risk and sometimes fails to provide the correct diagnosis because the lesions in NCGN are often focal and can be missing from a small biopsy specimen (Madio, Kidney Int. 38:529, 1990). Furthermore, some cases of primary NCGN cannot be reliably classified.
Serologic tests have diagnostic value in some forms of RPGN. In particular, patients exhibiting RPGN often have circulating auto-antibodies directed against neutrophils and monocytes. The presence of these auto-antibodies, generally referred to as anti-neutrophil cytoplasm antibodies (ANCA), has been used as a diagnostic tool. ANCA are detected by means of an indirect immunofluorescence assay using ethanol fixed normal human neutrophils as a substrate.
Two staining patterns have been described: (1) cytoplasmic, and (2) nuclear or perinuclear (Andrassy et al., Nephron 49:257-258, 1988). The cytoplasmic pattern is detected in the majority of patients with active Wegener's granulomatosis (Van der Woude et al., Lancet 1:806,1985), and is occasionally found in other patients with primary NCGN or microscopic polyarteritis nodosa (Jennette et al., Am. J. Pathol. 135:921,1987, Cohen et al., Kidney Int. 37:799, 1990). The autoantigen associated with the cytoplasmic staining pattern is a soluble protein of 27-29 kilodalton (kD) localized to the primary or secondary granule fractions (Gross et al., Lancet 1:1488, 1987; Goldschmeding, Kidney Int. 32:779, 1987). In contrast, the nuclear or perinuclear staining pattern is seen in only a very small percentage of patients diagnosed as having Wegener's granulomatosis. This pattern, which often results from antibodies against myeloperoxidase (MPO), an antigen that is artificially redistributed in the preparation of neutrophils (Falk et al., N. Eng. J. Med. 318:1651), is found in some patients with primary NCGN or microscopic polyarteritis nodosa (Andrassy et al., Clin. Nephrol. 32:159, 1989; Gans et al., Lancet 1:269, 1989). Because of these distinct staining patterns the indirect immunofluorescence assay can be a useful diagnostic tool. However, analysis of the staining patterns is difficult, and it has been recommended that at least 1000 sera samples be examined before an individual is qualified to interpret the staining patterns (Rasmussen et al., Lancet 1:706, 1988). A simpler and more readily quantifiable assay for the auto-antibodies associated with these conditions would allow earlier and more accurate diagnosis, and would facilitate early therapeutic intervention. Accurate diagnosis is particularly important because the treatment of these disorders involves potentially toxic drugs, and clinicians may be reluctant to proceed without a definite diagnosis. More accurate diagnosis may also provide data that will contribute to an understanding of the pathogenesis of these apparently related diseases.